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Chapter 1

Controlled Drug Delivery: Present and Future 1

K i n a m Park and Randall J. M r s n y

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1Purdue University School of Pharmacy, West Lafayette, IN 47907 2Department of Pharmaceutical Research and Development, Genentech Inc., South San Francisco, CA 94080

Downloaded by UNIV OF SUSSEX on May 11, 2012 | http://pubs.acs.org Publication Date: May 15, 2000 | doi: 10.1021/bk-2000-0752.ch001

Advances in controlled release drug delivery systems have been largely based on advances in functional polymers. However, the future of controlled release dosage forms will likely be heavily dependent upon an increased understanding of protein chemistry and cell biology principles. As our understanding increases on how cells function in normal and disease states and what limits the actions of potential therapeutics, the possibility of designing delivery technologies into a therapeutic offers tremendous potential for clinical interventions with maximal efficacy and minimal side effects. Genes and gene products and peptide and protein drugs will be the drugs of choice in the future due to their exquisitely specific bioactivities. Delivery approaches for these classes of therapeutics will likely come in many forms, some of which may be radically new. As in the current millennium, the success of delivery approaches in the next millenium will require interdisciplinary approaches.

Controlled release drug delivery technologies have made quantum advances in the last three decades from primitive delayed-release dosage forms in 1960's to highly sophisticated self-regulated delivery systems in 1990's . Drugs can now be delivered at zero-order for periods ranging from days to years. Such technology advances have produced many clinically useful controlled release dosage forms and have provided new lives for many existing drugs. Injectable lipid-based systems have recently been shown to have striking clinical advantages over previous formulations for reducing the overt side-effects associated with the administration of several existing therapeutic agents that are extremely toxic. Advances in areas such as biotechnology have now brought new and more difficult challenges (or opportunities) in controlled drug 1

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© 2000 American Chemical Society In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

3 delivery that will require more than the sustained release approaches previously provided by the highly successful lipid-based systems. It is now possible to produce oligonucleotide, peptide and protein drugs in large quantities, and non-parenteral delivery of such drugs has become a major issue " . Gene therapy also now appears to be clinically feasible and effective delivery of genes to specific target sites is an unmet medical need. Scientists in the controlled release area have been very creative and effective in developing new technologies for such new challenges. On the occasion of transitioning into a new millennium, we examine the current status and future prospects of the controlled release technologies and their potential applications.


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Issues in the Development of Controlled Release Dosage Forms Development of controlled release drug delivery systems requires simultaneous consideration of several factors, such as the drug property, route of administration, nature of delivery vehicle, mechanism of drug release, ability of targeting, and biocompatibility (Fig. 1). Due to extensive interdependency of those factors, it is not easy to establish a sequential process for designing a controlled release dosage form. Choice of one factor in Fig. 1 is likely to affect and/or to be affected by other factors. Let's consider developing a gene delivery system. Genes are macromolecules and successful gene therapy requires more specific cellular targeting than therapies which use other forms of drugs. A n ideal gene delivery system should allow gene to find the target cell, penetrate the cell membrane, and go into the nucleus. Since genes should not be released until they reach the target cellular component, release has to be delayed. Furthermore, one has to decide whether to release genes only once or repeatedly through a predetermined period of time. Currently, attenuated, living viruses are most effective in cell transfection, and the use of live vectors leads to the issue of neutralizing immunological responses. To relieve such issues of biocompatibility, one can employ non-living vectors, but then the targeting and transfection efficiency will be low. At present (at least for now before in the 21st Century), the most common route of gene therapy adminstration is by parenteal injection and syringable microparticulate delivery systems are a reasonable choice. In the future, it may be possible for other delivery technologies to be used i f the size, composition or targeting capacity of genes can be modified. In any regard, the selection of a delivery system involves an iterative process where factors of adminsration route and dose are critical.

Current Controlled Release Technologies Smart Polymers Much of the current technology of controlled drug delivery is primarily based on polymers having various properties. Polymer, commonly known as "plastic" to the

In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

4 public, has been one of the main driving forces shaping the cultural history of the 20th Century . The history of controlled drug delivery, of course, has been based on the evolution of polymers. From simple pH-sensitive polymers commonly used for enteric coating to sol-called "smart" polymers used in self-regulated (or modulated) drug delivery systems, polymers have made it possible to design controlled release dosage forms with a variety of release profiles . It is the polymer that has also made it possible to deliver heterologous cells releasing desired bioactive agents without immune responses in humans . Undoubtedly, future advances in controlled drug delivery will continue to depend on the advances in new polymeric materials, such as synthetic polymers with novel functions and protein mimetics . There are a number of polymers that have been used in drug delivery and known to be safe which are comprised of generally regarded as safe (GRAS) materials. Since few pharmaceutical companies wants to go through the lengthy regulatory processes required for approval of new polymers by Food and Drug Administration (FDA), only a limited number of polymers are currently used in the development of clinical controlled release drug delivery systems. Unfortunately, most of the recently developed smart polymers do not have a long history of safe use. Thus these materials are not considered as G R A S materials, which puts serious limitations in the practical application of smart polymers. Despite this, numerous new polymers have been developed and tested for controlled drug delivery. Since the benefit of using smart polymers should be much greater than the potential risk, one may justify the use of these new polymers for advanced controlled drug delivery. 5

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Factors Important to Controlled Drug Delivery Of the many routes of drug delivery, oral administration has been dominant. Oral delivery is simply the most convenient mode of drug delivery, and the first choice in selecting the delivery route. This will not change anytime soon. Oral controlled drug delivery, however, has a number of limitations posed by human physiology. Only small molecular drugs stable in the hostile environment of the gut can be delivered by the oral route. Appreciable amounts of large molecular drugs, such as proteins, cannot be absorbed intact from the GI tract. In addition, relatively short GI transit time, in the order of several hours, limits the drug delivery to only 12 hours or so, except for drugs that are absorbed well in the large intestine. Limitations in oral delivery have had a significant influence in developing small molecular drugs based on protein drugs (see below). Recent efforts exploring alternative routes for peptide and protein drug delivery have resulted in some promising outcomes. Clinical studies with selected maeromolecular drugs (including insulin) have suggested that both pulmonary and gastrointestinal routes may in fact be useful in the delivery of drugs previously consdered too large for significant absorption. Targeting of drugs/delivery systems to specific tissues and cells in the body is an area requiring major breakthroughs. History shows that targeting of cancer drugs to tumors and genes to defected cells requires much more than simply attaching


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Drug Property


Molecular Weight Stability Solubility

Λ

Administration Route

Biocompatibility

Oral, Pulmonary, Transdermal, Implantable, Parenteral

Mutual effects between body and dosage form

Targeting

Delivery Vehicle

Organ Tissue Cell Cell components

Polymer Size & Shape Cell Tissue Release Mechanism Continuous delivery Modulated delivery Duration of Release

Figure 1. Interdependent factors important in the design of controlled drug delivery systems. The pathophysiology of a disease also plays a critical role in the definition of thefinalgoal of this scheme - development of an optimal dosage form.


6 antibodies against molecules present on target cells. Coating delivery systems, which are most likely nano- and micro-particulates, with poly(ethylene glycol) (PEG) is known to increase the blood circulation time substantially . PEGylated dosage forms, i f equipped with a proper homing mechanism, may have a better chance of targeting due to their longer circulation times. The issue of biocompatibility was brought to our attention after recent episodes associated with silicone rubber-based implantable devices (e.g., Norplant). Silicone rubber has long been presumed to be totally biocompatible. Yet, the body responds to silicone implants by forming a fibrous capsule around the implanted device similar to any foreign body. Since long-term drug delivery on the order of months and years inevitably requires implantation of controlled release dosage forms, biocompatibility of implanted material may be the determining factor for the success of their clinical use. Development of new polymers or modification of existing polymers for improved biocompatibility requires a better understanding on the body's reaction toward an implanted artificial material .


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Tissue Engineering as Drug Delivery Vehicles 12

Tissue engineering has made landmark advances in the recent past . Not only has there been a new appreciation for geometries of the framework required to recreate vital tissue and organ architecture, but cell culture methods to allow for the simultaneous growth of several cell types have been identified. With such recent successes in organ and tissue replacement efforts, it is easy to be extremely optimistic about what the next millennium might hold in this area. Not only have complex organs been prepared in the lab and been shown to function properly following implantation , the knowledge base obtained from other arenas will feed important information into this field. For example, a number of genetic manipulation studies in mice where specific genes are either knocked out or knocked in have led to the identification of factors critical to the growth and development of various organs and tissues. Many of these observations came as a surprise because the role played by these factors is many times very transient and not sustained in the mature organ or tissue. With such knowledge it may soon be possible to build artificial pancreas releasing insulin in response to changes in glucose levels in blood for diabetic patients. Thus, tissue engineering holds great promise in the future of controlled drug delivery. 1 3

Challenges in Controlled Release Technologies Non-parenteral Delivery of Peptide and Protein Drugs Although extensive efforts have been and will be made to reduce critical peptide and protein functions to orally bioavailable small molecular mimetics, many peptide and protein therapeutics will not be able to be easily emulated in this way. Recent, extensive efforts have gone into identifying and validating non-parenteral delivery methods that provide anIn improved delivery of peptide and protein drugs. These Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

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approaches have demonstrated that the mucosal barriers (primarily respiratory and gastrointestinal tract) can be a site of successful peptide and protein delivery where significant biochemical, physiological and physical barriers established by these mucosal surfaces have been surmounted. The actual mechanisms by which these barriers have been overcome is not completely clear at this time and additional studies may better define critical components which might be manipulated to make transmucosal delivery a primary method of delivering peptide and protein therapeutics. Although in-roads have been made to overcome mucosal barriers for the delivery of peptides and proteins, the desired delivery profile is typically rapid and short-lived. Delivery of peptide and protein drugs by non-parenteral route needs to be followed by more continuous or long-lived delivery profiles using biodegradable polymer-based systems.

Targeting of Peptide and Protein Drugs Adequate controlled delivery of peptides and proteins is frequently critical to their clinical success. Up to this point successful peptide and protein therapeutics are typically endocrine factors which are secreted at one location in the body but which act at distant, and frequently multiple, sites of the body. Such molecules can be equally effective in their biological actions relative to their side-effect profiles whether they are delivered by traditional parenteral injections, polymer-based depots, or trans-mucosal methods. Many peptides and proteins, however, act more locally, being secreted by a cell to act on itself as an autocrine factor or on adjacent cells as a paracrine factor. These factors are not typically intended to circulate systemically as typical endocrine factors, and the serious side effects associated with the systemic delivery of such factors have severely limited the clinical utility of many promising molecules (e.g., interferons and interleukins). Presently, an improved appreciation of these systemic side effect issues has driven interest in peptide and protein delivery approaches other than parenteral injection. The capacity to potentially deliver peptides and proteins at specific epithelia could provide highly focused concentrations similar to that achieved by a local delivery. The delivery profile desired for maximal therapeutic use of peptides and proteins may be possible through improved targeting.

Delivery of Oligonucleotides and Genes. The human genome project will not only drive the identification of new protein and peptide entities for therapeutic application, but also result in the identification of disease-causing defective genes. Replacing of a defective gene or merely introducing the correct form is the promise of gene therapy. These therapeutic approaches are likely to have tremendous impact in the next millennium since they would hopefully eliminate the need for continued therapy to deal with disease symptoms or could be used to prophylactically protect an individual against a condition (e.g., cancer, heart disease, etc.) for which they are genetically pre-disposed. The uptake, integration and expression of introduced genetic material, however, is extremely challenging. As one might imagine, the body has established significant barriers to the random uptake of In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

8 genetic materials. This is an important protective mechanism since various cells of the body are confronted daily with the genetic material from disrupted pathogens and/or diseased cells . A number of approaches, such as liposomes, lipid complexes, polymers and viral vectors, have been taken to overcome the challenges of genetic material delivery and uptake . To date, viral vectors have demonstrated promise in clinical settings but have been used under controlled conditions where the transfection either occurred in vitro and the transfected cells were returned to the body or where the vector was applied in vivo to a mucosal surface. Only a few viral vectors have been used to date, but great advances may come from the identification and application of viral vectors with highly specific tropisms. For example, specific delivery of genes encoding pain-killing proteins to the central nervous system for patients suffering from conditions of chronic pain appears to be possible . The success of cloning of mammals from somatic cells brought new possibilities in gene delivery. The introduction of components associated with sperm nuclei has been shown to facilitate the expression of introduced somatic genetic material. Conjugation of oligonucleotides with peptides can improve cellular uptake in antisense applications. Many of these findings were unanticipated and point to the likelihood of even more unanticipated, but extremely useful findings in the near future. Some of these findings will likely come in the progression of knowledge gained about the use of viral vectors to deliver genetic material. 14

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Future Prospects

Development of Non-protein Mimetic Drugs Over the last millennium, two forms of drug delivery have dominated. Small, easily absorbed agents have been the more readily acceptable form while injection of macromolecules has been a less desired, but tolerated form of delivery. Small molecules can readily enter the body at a mucosal surface or across the skin through passive mechanisms. Small molecular drugs are frequently identified surreptitiously through screens of massive chemical libraries. Ultimate success of these compounds in clinical settings commonly requires satisfying two general parameters. The first parameter is that once the drug is absorbed it has to reach the target cell, tissue of organ without extensive modification or destruction and induce an action at the target sufficient for the desired activity. Appropriate pharmacokinetic and pharmacodynamic profiles are typically obtained for only a few of the hundreds or thousands of potential compounds identified in these screens. A l l too often additional chemical modification of otherwise promising compounds is required and to obtain lead molecules with desired (or even acceptable) pharmacokinetic and pharmacodynamic profiles. The second parameter of clinical success for a small molecule is the identification of an acceptable therapeutic window. This is a range of drug concentrations bracketed by a lack of effect at one extreme and toxicity at the other. The chances of finding an acceptable therapeutic window for a new small



9 molecule drug is positively correlated with the selectivity of action by that drug. Although initial drug screening using in vitro model systems can sometimes be used to select for certain aspects of drug selectivity, ultimately in vivo studies are required to identify or rule out unanticipated drug actions and this approach has become a primary screening approach for drug selection. Advances in recombinant biotechnology over the last twenty years have allowed for the development of new peptide and protein therapeutics and have also provided a much different approach to the identification of promising small molecular drug candidates. Instead of random screening of chemical libraries in vivo using various animal models, the identification and large-scale production of critical therapeutic peptide and protein targets can now be accomplished. This new approach of drug screening is currently being used to establish mechanism(s) of drug action but also to provide a clearer understanding of potential side effect profiles. From these studies, it has become clear that the peptide and protein therapeutics are dramatically more selective than small molecular drugs which emulate their actions. A likely explanation for this outcome is that most peptide and proteins function selectively by initiating multiple contact sites on a target or targets to achieve the desired action. One parameter of small molecular drugs is that of size, with the an upper limit in size of about 400 g/mole. Molecules constrained by this size limitation cannot typically bridge required molecular distances essential to establish such specificity . Efforts to reduce the size of molecules while maintaining specificity have further established apparent limits in the molecular requirements of non-protein mimetics. 17

New Drug Modalities - New Drug Delivery Approaches The prospects of better defining the specificity of small molecular drugs and improving the delivery options of peptides and proteins appears promising. Such advances will be driven not only by a wealth of critical information generated by the Human Genome Project but also by the identification of technologies which allow for new and/or better screening methods and a clarification of therapeutic targets. As secrets of the human genome become known, not only will new therapeutic targets be identified but it will be possible to better clarify the actions of current therapeutics to drive their refinement. Additionally, the information derived from sequencing the human genome will provide the basis to advances in critical areas of information associated with the development of new proteins and peptides as well as small molecule therapeutics and even new classes of therapeutic agents. Thus, we would anticipate that the spectrum of drug modalities utilized in the next millennium will likely include new applications for carbohydrates, lipids and nucleotide-based drug molecules. Novel physical and chemical characteristics of these new classes of compounds should drive new approaches in drug delivery and a re-examination of established methods. Ultimately, successful therapeutic application(s) from each of these chemical classes will likely rely on appropriate local and/or targeted drug delivery technologies to add selectively and increase therapeutic opportunities.


10 Understanding Structures of Peptide and Protein Drugs Peptides and proteins are composed of linear polymers of amino acids, with peptides containing usually less than 20 residues and proteins being composed of more. Although stable solution structures for peptides of less than 20 amino acids have been determined, this break-point roughly relates to the presumed differences between proteins and peptides where the former is likely to have a more defined and stable solution structure than the latter. A critical role for the application of any protein or peptide therapeutic is that it can either acquire and/or maintain the proper structure for its desired biological activity . One area where advances in the next millennium will significantly impact the field of therapeutic proteins and peptides is that of solution structure calculations. Currently, only a few poorly defined rules of protein folding based upon amino acid sequence are understood; but even the exceptions to these rules are poorly understood. At present, solution structure information has been obtained for some peptides and crystal structure information has been acquired for some proteins. However, critical rules of the protein and peptide structure/fimction will likely come from solution structures of proteins during interactions with their functional mate (e.g., a receptor, enzyme substrate, etc.) since these interactions could easily involve induced fit events. Established rules of protein folding will expedite the identification and development of protein and peptide therapeutics as well as small molecule drugs designed to best emulate critical actions of these proteins and peptides. Such structure/function information about peptides and proteins may lead to the optimization of stability both in formulations and following administration. Further, defective or altered proteins such as enzymes, ion channels and cell-surface receptors involved in the modified cellular pathways associated with disease states will be better defined. With this more complete data set, a clearer understanding of disease will be possible and the selection of optimal sites for therapeutic intervention will be better appreciated. This more complete understanding may also lead to a more logical effort to identify effective small molecule therapeutics capable of affecting or modulating a disease state previously defined only by these protein and peptide interactions. A l l information will be critical in formulation of long-term delivery systems for protein drugs and non-protein mimetics.


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Targeting to Intracellular Sites Many opportunities for drug delivery in the next millennium will likely come from unanticipated scientific observations. In the area of intracellular delivery and targeting, one of those surprising findings was already made in this millennium. The observation that some growth factors and polypeptide hormones and toxins can target intracellular targets such as the nucleus of cells following interaction with the external surface of the plasma membrane opens up an unprecedented possibility to access the cytoplasm of cells. No longer would small molecules be required to access the interior of cells. With the additional knowledge of how proteins can be sequestered at specific organelles and structures within cells, it seems likely that pharmaceuticals of the new millennium may include protein conjugate or chimera molecules which can cross the plasma membrane, access the cell's cytoplasm and target to specific In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

11 intracellular sites. Although many questions remain to be answered before significant applications of such an approach can be used to delivery a therapeutic agent, the concept of such a delivery approach is indicative of what may be possible in the next millennium.


Acknowledgments We thank the sponsors of the symposium: Abbott Labatories (Hospital Products Division), the A C S Polymer Chemistry Division, Amgen, Bristol-Myers Squibb Co., Glaxo Wellcome Inc., Genentech Inc., GeneMedicine Inc., Immunex Inc., Merck Research Labs, Pharmacia & Upjohn, Schering-Plough Corp., Soffmova Inc., and Yamanouchi Shaklee Pharma.

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